RESUMEN
BACKGROUND: The cell surface glycoprotein E-cadherin (CDH1) is a key regulator of adhesive properties in epithelial cells. Germline mutations in CDH1 are well established as the defects underlying hereditary diffuse gastric cancer (HDGC) syndrome, and an increased risk of lobular breast cancer (LBC) has been described in HDGC kindreds. However, germline CDH1 mutations have not been described in patients with LBC in non-HDGC families. This study aimed to investigate the frequency of germline CDH1 mutations in patients with LBC with early onset disease or family histories of breast cancer without DGC. METHODS: Germline DNA was analysed in 23 women with invasive lobular or mixed ductal and lobular breast cancers who had at least one close relative with breast cancer or had themselves been diagnosed before the age of 45 years, had tested negative for a germline BRCA1 or BRCA2 mutation, and reported no personal or family history of diffuse gastric cancer. The full coding sequence of CDH1 including splice junctions was amplified using PCR and screened for mutations using DHPLC and sequencing. RESULTS: A novel germline CDH1 truncating mutation in the extracellular portion of the protein (517insA) was identified in one woman who had LBC at the age of 42 years and a first degree relative with invasive LBC. CONCLUSIONS: Germline CDH1 mutations can be associated with invasive LBC in the absence of diffuse gastric cancer. The finding, if confirmed, may have implications for management of individuals at risk for this breast cancer subtype. Clarification of the cancer risks in the syndrome is essential.
Asunto(s)
Neoplasias de la Mama/genética , Cadherinas/genética , Carcinoma de Células Grandes/genética , Codón sin Sentido , Mutación de Línea Germinal , Síndromes Neoplásicos Hereditarios/genética , Adulto , Neoplasias de la Mama/química , Cadherinas/análisis , Cadherinas/deficiencia , Carcinoma Ductal de Mama/genética , Carcinoma de Células Grandes/química , Metilación de ADN , Femenino , Heterogeneidad Genética , Humanos , Pérdida de Heterocigocidad , Invasividad Neoplásica , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/genética , Linaje , Neoplasias Gástricas/genéticaAsunto(s)
Inhibidores de Proteasas , Tripsina/metabolismo , alfa-Macroglobulinas/metabolismo , Animales , Bovinos , Quimotripsinógeno/metabolismo , Perros , Activación Enzimática , Humanos , Cinética , Páncreas/enzimología , Elastasa Pancreática/metabolismo , Plantas/enzimología , Inhibidores de Proteasas/farmacología , Unión Proteica , Inhibidor de la Tripsina de Soja de Bowman-Birk/farmacologíaRESUMEN
Hypersensitivity reactions have been reported as limiting side effect in patients re-exposed to carboplatin for relapsed gynecologic malignancy. This study analyzed the incidence, clinical features, management, and outcome of carboplatin-associated hypersensitivity reactions. We performed a retrospective study and analyzed medical records of all gynecological cancer patients treated with carboplatin in our institution from 2000 to 2003. No hypersensitivity reactions were observed in 171 patients during the first carboplatin-containing chemotherapy. All six carboplatin-associated hypersensitivity reactions occurred in 69 patients who were re-exposed to carboplatin (9%). The median number of carboplatin cycles prior to hypersensitivity reaction was nine (range, 8-13). Cisplatin rechallenge was performed in five patients, and no hypersensitivity occurred. An increase in neurotoxicity (National Cancer Institute Common Toxicity Criteria grade 2) was documented in two patients who had residual neurotoxicity grade 1 due to prior taxane treatment. Cisplatinum rechallenge is a feasible strategy to overcome carboplatin hypersensitivity. However, close monitoring of neurotoxicity is necessary, particularly in patients with residual neurotoxicity due to prior platinum- and taxane-containing chemotherapy.